The most common indication for allogeneic hematopoietic stem cell transplantation (HCT) in children is high- risk acute leukemia, with equal distribution between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). With advances in risk-classification, donor tissue typing, conditioning regimen, and transplant care, outcomes for transplant recipients have steadily improved over time. Thus, HCT is now a well-accepted therapy for children with many subtypes of high-risk ALL and AML. A key question remains regarding the best approach to the 40-50% of children who do not have matched donors available. Encouraging data have been published recently using unrelated human leukocyte antigen (HLA)-mismatched umbilical cord blood (UCB) in both the adult and pediatric populations. Excellent outcomes were also observed with killer-cell immunoglobulin-like receptor (KIR)-mismatched HLA-haploidentical HCTs. However, no direct comparisons of these two stem cell sources have been performed in children. In this proposal, five participating institutions of the Pediatric Blood and Marrow Transplant Consortium (PBMTC) will examine the feasibility and outcome of HCTs in patients who will receive an HLA-mismatched graft because a matched donor is not available. Based on the availability of a KIR-mismatched parental donor, the participant will be biologically assigned to receive either a KIR-mismatched haploidentical donor HCT or an HLA-mismatched UCB HCT. Specific Aim 1 will assess the overall survival 1 year after transplantation. The primary hypothesis is that T-cell-depleted, favorably KIR-mismatched, haploidentical HCT in AML and ALL patients lacking fully matched related or unrelated donors is feasible and will result in an increase in the survival rate at 1 year by 20% compared with mismatched UCB. Furthermore, recent data suggest that patients who received a donor graft containing the functionally stronger KIR2DL1 alleles with arginine at amino acid position 245 (KIR2DL1-R245) had better survival and a lower relapse rate than those who received a donor graft that contained only the functionally weaker KIR2DL1 allele with cysteine at the same position (KIR2DL1-C245). Therefore, in Specific Aim 2, we will estimate the effect of donor KIR2DL1 polymorphism on the outcome of HCTs in the context of this clinical trial. The primary hypothesis is that HCT using a KIR2DL1-R245 donor will result in a better survival rate at 1 year than those using a KIR2DL1-C245 graft. If successfully completed, this study will provide high-quality data essential for future improvement of transplant strategies for the large number of children without an HLA- matched donor.